tbuckley/cabot-search huggingface dataset:
Interaction of Cardiovascular Nonmodifiable Risk Factors, Comorbidities and Comedications With Ischemia/Reperfusion Injury and Cardioprotection by Pharmacological Treatments and Ischemic Conditioning
Authors: Péter Ferdinandy, Ioanna Andreadou, Gary F. Baxter, Hans Erik Bøtker, Sean M. Davidson, Dobromir Dobrev, Bernard J. Gersh, Gerd Heusch, Sandrine Lecour, Marisol Ruiz-Meana, Coert J. Zuurbier, Derek J. Hausenloy, Rainer Schulz
Journal: Pharmacological Reviews (2022)

Preconditioning, postconditioning, and remote conditioning of the myocardium enhance the ability of the heart to withstand a prolonged ischemia/reperfusion insult and the potential to provide novel therapeutic paradigms for cardioprotection. While many signaling pathways leading to endogenous cardioprotection have been elucidated in experimental studies over the past 30 years, no cardioprotective drug is on the market yet for that indication. One likely major reason for this failure to translate cardioprotection into patient benefit is the lack of rigorous and systematic preclinical evaluation of promising cardioprotective therapies prior to their clinical evaluation, since ischemic heart disease in humans is a complex disorder caused by or associated with cardiovascular risk factors and comorbidities. These risk factors and comorbidities induce fundamental alterations in cellular signaling cascades that affect the development of ischemia/reperfusion injury and responses to cardioprotective interventions. Moreover, some of the medications used to treat these comorbidities may impact on cardioprotection by again modifying cellular signaling pathways. The aim of this article is to review the recent evidence that cardiovascular risk factors as well as comorbidities and their medications may modify the response to cardioprotective interventions. We emphasize the critical need for taking into account the presence of cardiovascular risk factors as well as comorbidities and their concomitant medications when designing preclinical studies for the identification and validation of cardioprotective drug targets and clinical studies. This will hopefully maximize the success rate of developing rational approaches to effective cardioprotective therapies for the majority of patients with multiple comorbidities. <h3>Significance Statement</h3> Ischemic heart disease is a major cause of mortality; however, there are still no cardioprotective drugs on the market. Most studies on cardioprotection have been undertaken in animal models of ischemia/reperfusion in the absence of comorbidities; however, ischemic heart disease develops with other systemic disorders (e.g., hypertension, hyperlipidemia, diabetes, atherosclerosis). Here we focus on the preclinical and clinical evidence showing how these comorbidities and their routine medications affect ischemia/reperfusion injury and interfere with cardioprotective strategies.
Association of Lipoprotein(a) Levels With Incidence of Major Adverse Limb Events
Authors: Alexis F. Guédon, Jean-Baptiste De Freminville, Tristan Mirault, Nassim Mohamedi, Bastien Rance, Natalie Fournier, Jean-Louis Paul, Emmanuel Messas, Guillaume Goudot
Journal: JAMA Network Open (2022)

High lipoprotein(a) (Lp[a]) levels are involved in the development of cardiovascular events, particularly in myocardial infarction, stroke, and peripheral artery disease. Studies assessing the Lp(a) levels associated with adverse lower-limb events are lacking.To assess the association between Lp(a) levels and incidence of major adverse limb events in unselected hospitalized patients.This large retrospective monocentric cohort study was conducted from January 1, 2000, to December 31, 2020. Data were derived from the clinical information system of the Hôpital Européen Georges-Pompidou, a Paris-based university hospital. Patients who underwent at least 1 Lp(a) measurement at the center during the study period were included. Patients who had no follow-up data or who had the first Lp(a) measurement after the study outcome had occurred were excluded. Data analyses were performed from May 2021 to January 2022.The primary outcome was the first inpatient major adverse limb event, defined as a major amputation, peripheral endovascular revascularization, or peripheral surgical revascularization, during follow-up. Secondary outcomes included individual components of the primary outcome. Lipoprotein(a) levels were categorized as follows: normal (<50 mg/dL), high (50 to <134 mg/dL), and very high (≥134 mg/dL); to convert Lp(a) values to milligrams per liter, multiply by 0.1.A total of 16 513 patients (median [IQR] age, 58.2 [49.0-66.7] years; 9774 men [59.2%]) were included in the cohort. The median (IQR) Lp(a) level was 24 (10.0-60.0) mg/dL. The 1-year incidence of major adverse limb event was 2.44% in the overall population and 4.54% among patients with very high Lp(a) levels. High (adjusted accelerated failure time [AFT] exponential estimate: 0.43; 95% CI, 0.24-0.78; Benjamini-Hochberg-corrected P = .01) and very high (adjusted AFT exponential estimate: 0.17; 95% CI, 0.07-0.40; Benjamini-Hochberg-corrected P < .001) Lp(a) levels were independently associated with an increased risk of major adverse limb event.Results of this study showed that higher Lp(a) levels were independently associated with an increased risk of a major adverse limb event in hospitalized patients. The Lp(a) measurement needs to be taken into account to improve lower-limb vascular risk assessment.
Association of Pack-Years of Cigarette Smoking With Survival and Tumor Progression Among Patients Treated With Chemoradiation for Head and Neck Cancer
Authors: Sung Jun Ma, Han Yu, Brian Yu, Olivia Waldman, Michael Khan, Udit Chatterjee, Sharon Santhosh, Jasmin Gill, Austin J. Iovoli, Mark Farrugia, Alina Shevorykin, Ellen Carl, Kimberly Wooten, Vishal Gupta, Ryan McSpadden, Moni A. Kuriakose, Michael R. Markiewicz, Ayham Al-Afif, Wesley L. Hicks, Mary E. Platek, Mukund Seshadri, Christine Sheffer, Graham W. Warren, Anurag K. Singh
Journal: JAMA Network Open (2022)

After 10 pack-years of smoking was initially established as a threshold for risk stratification, subsequent clinical trials incorporated it to identify candidates for treatment deintensification. However, several recent studies were unable to validate this threshold externally, and the threshold for smoking exposure remains unclear.To estimate the threshold of pack-years of smoking associated with survival and tumor recurrence among patients with head and neck cancer.This single-institution, cohort study included patients with nonmetastatic head and neck cancer receiving chemoradiation from January 2005 to April 2021. Data were analyzed from January to April 2022.Heavy vs light smoking using 22 pack-years as a threshold based on maximizing log-rank test statistic.Overall survival (OS), progression-free survival (PFS), locoregional failure (LRF), and distant failure (DF).A total of 518 patients (427 male [82.4%]; median [IQR] age, 61 [55-66] years) were included. Median (IQR) follow-up was 44.1 (22.3-72.8) months. A nonlinear Cox regression model using restricted cubic splines showed continuous worsening of OS and PFS outcomes as pack-years of smoking increased. The threshold of pack-years to estimate OS and PFS was 22. Cox multivariable analysis (MVA) showed that more than 22 pack-years was associated with worse OS (adjusted hazard ratio [aHR] 1.57; 95% CI, 1.11-2.22; P = .01) and PFS (aHR, 1.38; 95% CI, 1.00-1.89; P = .048). On Fine-Gray MVA, heavy smokers were associated with DF (aHR, 1.71; 95% CI, 1.02-2.88; P = .04), but not LRF (aHR, 1.07; 95% CI, 0.61-1.87; P = .82). When 10 pack-years of smoking were used as a threshold, there was no association for OS (aHR, 1.23; 95% CI, 0.83-1.81; P = .30), PFS (aHR, 1.11; 95% CI, 0.78-1.57; P = .56), LRF (aHR, 1.19; 95% CI, 0.64-2.21; P = .58), and DF (aHR, 1.45; 95% CI, 0.82-2.56; P = .20). Current smoking was associated with worse OS and PFS only among human papillomavirus (HPV)-positive tumors (OS: aHR, 2.81; 95% CI, 1.26-6.29; P = .01; PFS: aHR, 2.51; 95% CI, 1.22-5.14; P = .01).In this cohort study of patients treated with definitive chemoradiation, 22 pack-years of smoking was associated with survival and distant metastasis outcomes. Current smoking status was associated with adverse outcomes only among patients with HPV-associated head and neck cancer.
In-depth analysis of alternative splicing landscape in multiple myeloma and potential role of dysregulated splicing factors
Authors: Anil Aktas Samur, Mariateresa Fulciniti, Herve Avet-Loiseau, Michael A. Lopez, Sanika Derebail, Jill Corre, Stephane Minvielle, Florence Magrangeas, Philippe Moreau, Kenneth C. Anderson, Giovanni Parmigiani, Mehmet K. Samur, Nikhil C. Munshi
Journal: Blood Cancer Journal (2022)

Splicing changes are common in cancer and are associated with dysregulated splicing factors. Here, we analyzed RNA-seq data from 323 newly diagnosed multiple myeloma (MM) patients and described the alternative splicing (AS) landscape. We observed a large number of splicing pattern changes in MM cells compared to normal plasma cells (NPC). The most common events were alterations of mutually exclusive exons and exon skipping. Most of these events were observed in the absence of overall changes in gene expression and often impacted the coding potential of the alternatively spliced genes. To understand the molecular mechanisms driving frequent aberrant AS, we investigated 115 splicing factors (SFs) and associated them with the AS events in MM. We observed that ~40% of SFs were dysregulated in MM cells compared to NPC and found a significant enrichment of SRSF1, SRSF9, and PCB1 binding motifs around AS events. Importantly, SRSF1 overexpression was linked with shorter survival in two independent MM datasets and was correlated with the number of AS events, impacting tumor cell proliferation. Together with the observation that MM cells are vulnerable to splicing inhibition, our results may lay the foundation for developing new therapeutic strategies for MM. We have developed a web portal that allows custom alternative splicing event queries by using gene symbols and visualizes AS events in MM and subgroups. Our portals can be accessed at http://rconnect.dfci.harvard.edu/mmsplicing/ and https://rconnect.dfci.harvard.edu/mmleafcutter/ .
Transcolonic endoscopic ultrasound-guided fine-needle biopsy to diagnose a pancreatic tail adenocarcinoma in a patient with surgically altered anatomy
Authors: Yujiro Kawakami, Yoshiharu Masaki, Masahiro Taniguchi, Keisuke Ishigami, Ayako Murota, Masayo Motoya, Hiroshi Nakase
Journal: Endoscopy (2022)

Previous studies have demonstrated that endoscopic ultrasound-guided fine-needle aspiration/biopsy (EUS-FNA/B) is an efficient method for diagnosing pancreatic masses in patients with surgically altered anatomy [1], but it is sometimes difficult to visualize the target organs from the reconstructed route [2]. Echoendoscope manipulation challenges have restricted the approaches for EUS-FNA/B to the lower gastrointestinal tract, through the sigmoid colon and rectum [3]. Meanwhile, transcolonic EUS-FNA/B using forward-viewing echoendoscope or guidewire-assisted techniques have been reported [4] [5]. Herein, we report a case of pancreatic tail adenocarcinoma diagnosed by transcolonic EUS-FNB from the splenic flexure using an overtube method.
Lumen-apposing metal stent gastrojejunostomy for biliary drainage of an obstructive biliodigestive anastomosis
Authors: Moritz Haase, Jonas Rosendahl, Sebastian Krug
Journal: Endoscopy (2022)

A 68-year-old woman with pancreatic adenocarcinoma was referred to our department with jaundice and poor general condition. Surgical exploration 2 years previously had revealed an unresectable pancreatic head tumor and a biliodigestive anastomosis had been created. At presentation, the patient was receiving third-line chemotherapy and had locally advanced disease and peritoneal carcinomatosis. A computed tomography scan showed progressive disease, with obstruction of the biliodigestive anastomosis and consequent dilatation.
Composite Scaffolds of Gelatin and Fe<sub>3</sub>O<sub>4</sub> Nanoparticles for Magnetic Hyperthermia‐Based Breast Cancer Treatment and Adipose Tissue Regeneration
Authors: Rui Sun, Huajian Chen, Jing Zheng, Toru Yoshitomi, Naoki Kawazoe, Yingnan Yang, Guoping Chen
Journal: Advanced Healthcare Materials (2022)

Postsurgical treatment of breast cancer remains a challenge with regard to killing residual cancer cells and regenerating breast defects. To prepare composite scaffolds for postoperative use, gelatin is chemically modified with folic acid (FA) and used for hybridization with citrate-modified Fe3 O4 nanoparticles (Fe3 O4 -citrate NPs) to fabricate Fe3 O4 /gelatin composite scaffolds which pore structures are controlled by free ice microparticles. The composite scaffolds have large spherical pores that are interconnected to facilitate cell entry and exit. The FA-functionalized composite scaffolds have the ability to capture breast cancer cells. The Fe3 O4 /gelatin composite scaffolds possess a high capacity for magnetic-thermal conversion to ablate breast cancer cells during alternating magnetic field (AMF) irradiation. In addition, the composite scaffolds facilitate the growth and adipogenesis of mesenchymal stem cells. The composite scaffolds have multiple functions for eradication of residual cancer cells under AMF irradiation and for regeneration of resected adipose tissue when AMF is off.
Novel aspects in the pathophysiology and diagnosis of glomerular diseases
Authors: Andreas Kronbichler, Ingeborg Bajema, Duvuru Geetha, Marcus Säemann
Journal: Annals of the Rheumatic Diseases (2022)

Immune deposits/complexes are detected in a multitude of tissues in autoimmune disorders, but no organ has attracted as much attention as the kidney. Several kidney diseases are characterised by the presence of specific configurations of such deposits, and many of them are under a ‘shared care’ between rheumatologists and nephrologists. This review focuses on five different diseases commonly encountered in rheumatological and nephrological practice, namely IgA vasculitis, lupus nephritis, cryoglobulinaemia, anti-glomerular basement membrane disease and anti-neutrophil cytoplasm-antibody glomerulonephritis. They differ in disease aetiopathogenesis, but also the potential speed of kidney function decline, the responsiveness to immunosuppression/immunomodulation and the deposition of immune deposits/complexes. To date, it remains unclear if deposits are causing a specific disease or aim to abrogate inflammatory cascades responsible for tissue damage, such as neutrophil extracellular traps or the complement system. In principle, immunosuppressive therapies have not been developed to tackle immune deposits/complexes, and repeated kidney biopsy studies found persistence of deposits despite reduction of active inflammation, again highlighting the uncertainty about their involvement in tissue damage. In these studies, a progression of active lesions to chronic changes such as glomerulosclerosis was frequently reported. Novel therapeutic approaches aim to mitigate these changes more efficiently and rapidly. Several new agents, such as avacopan, an oral C5aR1 inhibitor, or imlifidase, that dissolves IgG within minutes, are more specifically reducing inflammatory cascades in the kidney and repeat tissue sampling might help to understand their impact on immune cell deposition and finally kidney function recovery and potential impact of immune complexes/deposits.
Proteoid biodynamers for safe mRNA transfection via pH-responsive nanorods enabling endosomal escape
Authors: Sangeun Lee, Sarah Nasr, Sari Rasheed, Yun Liu, Olga Hartwig, Cansu Kaya, Annette Boese, Marcus Koch, Jennifer Herrmann, Rolf Müller, Brigitta Loretz, Eric Buhler, Anna K.H. Hirsch, Claus-Michael Lehr
Journal: Journal of Controlled Release (2022)
Prospective Association of Daily Steps With Cardiovascular Disease: A Harmonized Meta-Analysis
Authors: Amanda E. Paluch, Shivangi Bajpai, Marcel Ballin, David R. Bassett, Thomas W. Buford, Mercedes R. Carnethon, Ariel Chernofsky, Erin E. Dooley, Ulf Ekelund, Kelly R. Evenson, Deborah A. Galuska, Barbara J. Jefferis, Lingsong Kong, William E. Kraus, Martin G. Larson, I-Min Lee, Charles E. Matthews, Robert L. Newton, Anna Nordström, Peter Nordström, Priya Palta, Alpa V. Patel, Kelley Pettee Gabriel, Carl F. Pieper, Lisa Pompeii, Erika Rees-Punia, Nicole L. Spartano, Ramachandran S. Vasan, Peter H. Whincup, Shengping Yang, Janet E. Fulton
Journal: Circulation (2022)

Taking fewer than the widely promoted "10 000 steps per day" has recently been associated with lower risk of all-cause mortality. The relationship of steps and cardiovascular disease (CVD) risk remains poorly described. A meta-analysis examining the dose-response relationship between steps per day and CVD can help inform clinical and public health guidelines. Eight prospective studies (20 152 adults [ie, ≥18 years of age]) were included with device-measured steps and participants followed for CVD events. Studies quantified steps per day and CVD events were defined as fatal and nonfatal coronary heart disease, stroke, and heart failure. Cox proportional hazards regression analyses were completed using study-specific quartiles and hazard ratios (HR) and 95% CI were meta-analyzed with inverse-variance-weighted random effects models. The mean age of participants was 63.2±12.4 years and 52% were women. The mean follow-up was 6.2 years (123 209 person-years), with a total of 1523 CVD events (12.4 per 1000 participant-years) reported. There was a significant difference in the association of steps per day and CVD between older (ie, ≥60 years of age) and younger adults (ie, <60 years of age). For older adults, the HR for quartile 2 was 0.80 (95% CI, 0.69 to 0.93), 0.62 for quartile 3 (95% CI, 0.52 to 0.74), and 0.51 for quartile 4 (95% CI, 0.41 to 0.63) compared with the lowest quartile. For younger adults, the HR for quartile 2 was 0.79 (95% CI, 0.46 to 1.35), 0.90 for quartile 3 (95% CI, 0.64 to 1.25), and 0.95 for quartile 4 (95% CI, 0.61 to 1.48) compared with the lowest quartile. Restricted cubic splines demonstrated a nonlinear association whereby more steps were associated with decreased risk of CVD among older adults. For older adults, taking more daily steps was associated with a progressively decreased risk of CVD. Monitoring and promoting steps per day is a simple metric for clinician-patient communication and population health to reduce the risk of CVD.
Role of multi-site sampling in the diagnosis of human Monkeypox
Authors: Alberto Rizzo, Davide Mileto, Davide Moschese, Caterina Candela, Alessandro Mancon, Andrea Giacomelli, Angelo Roberto Raccagni, Federica Salari, Maria Vittoria Cossu, Valeria Micheli, Antonella Castagna, Giuliano Rizzardini, Alessandra Lombardi, Silvia Nozza, Maria Rita Gismondo
Journal: Journal of Infection (2022)
Following the Omicron wave, the majority of children in England have evidence of previous COVID infection
Authors: C Oeser, H Whitaker, R Borrow, E Linley, S Tonge, C Rowe, A Otter, L Warrener, Cnj Campbell, S Ladhani, M Ramsay, K E Brown, G Amirthalingam
Journal: Journal of Infection (2022)
Effectiveness of covid-19 vaccines in adolescents and children
Authors: Pilar T V Florentino, Thiago Cerqueira-Silva, Manoel Barral-Netto, Enny S Paixão
Journal: BMJ (2022)

Although children and adolescents generally have a milder form of covid-19 than adults, some young people develop a severe illness leading to hospital admission or even death.Children can also develop complications, such as multisystem inflammatory syndrome in children and long covid syndrome. 1Furthermore, after the emergence of the omicron variant and the loosening of social distance measures, cases of covid-19 rose sharply among younger age groups, further disrupting schools and adding to communities' public health burdens.Perhaps unsurprisingly, and after careful scrutiny of safety data, public health authorities in many countries approved and strongly promoted covid-19 vaccination for adolescents and, later on, children.Castelli and colleagues' recent BMJ study (https://doi.org/10.1136/bmj-2022-073070) is a welcome addition to a rapidly growing literature evaluating the effectiveness of covid-19 vaccines in children and adolescents with real world data. 2 These age groups were under-represented in pre-authorisation trials of covid-19 vaccines.So as vaccination programmes for under 18s advanced, an important opportunity arose to quantify protection against mild and severe covid-19 achieved in these age groups and to determine whether it was somehow different from the protection achieved in adults.
Sentinel surveillance and epidemiology of Clostridioides difficile in Denmark, 2016 to 2019
Authors: Søren Persson, Hans Linde Nielsen, John Eugenio Coia, Jørgen Engberg, Bente Scharvik Olesen, Anne Line Engsbro, Andreas Munk Petersen, Hanne Marie Holt, Lars Lemming, Ea Sofie Marmolin, Turid Snekloth Søndergaard, Leif Percival Andersen, Mie Birgitte Frid Jensen, Camilla Wiuff, Gitte Sørensen, Sofie Holtsmark Nielsen, Eva Møller Nielsen
Journal: Eurosurveillance (2022)

Background Since 2008, Danish national surveillance of Clostridioides difficile has focused on binary toxin-positive strains in order to monitor epidemic types such as PCR ribotype (RT) 027 and 078. Additional surveillance is needed to provide a more unbiased representation of all strains from the clinical reservoir. Aim Setting up a new sentinel surveillance scheme for an improved understanding of type distribution relative to time, geography and epidemiology, here presenting data from 2016 to 2019. Methods For 2─4 weeks in spring and autumn each year between 2016 and 2019, all 10 Danish Departments of Clinical Microbiology collected faecal samples containing toxigenic C. difficile . Isolates were typed at the national reference laboratory at Statens Serum Institut. The typing method in 2016–17 used tandem-repeat-sequence typing, while the typing method in 2018–19 was whole genome sequencing. Results During the study period, the sentinel surveillance scheme included ca 14–15% of all Danish cases of C. difficile infections. Binary toxin-negative strains accounted for 75% and 16 of the 20 most prevalent types. The most common sequence types (ST) were ST2/13 (RT014/020) (19.5%), ST1 (RT027) (10.8%), ST11 (RT078) (6.7%), ST8 (RT002) (6.6%) and ST6 (RT005/117) (5.1%). The data also highlighted geographical differences, mostly related to ST1 and temporal decline of ST1 (p = 0.0008) and the increase of ST103 (p = 0.002), ST17 (p = 0.004) and ST37 (p = 0.003), the latter three binary toxin-negative. Conclusion Sentinel surveillance allowed nationwide monitoring of geographical differences and temporal changes in C. difficile infections in Denmark, including emerging types, regardless of binary toxin status.